GlyT1 inhibitors for use in the treatment of hematological disorders

Patent metadata

Field	Value
Publication number	US-9877963-B2
Application number	US-201615334722-A
Country	US
Kind code	B2
Filing date	Oct 26, 2016
Priority date	Apr 30, 2014
Publication date	Jan 30, 2018
Grant date	Jan 30, 2018

Abstract

The invention is related to compounds, which are GlyT1 inhibitors, for use in the treatment of hematological disorders, in particular for use in the treatment of sickle cell disease and thalassemia, or for the treatment of patients with iron overload syndromes, such as hereditary hemochromatosis.

First claim

We claim:

1. A method of treating a hematological disorder characterized by elevated cellular hemoglobulin (Hb) levels comprising administering to a patient in need thereof a therapeutically effective amount of a GlyT1 inhibitor of formula I:

wherein
R 1 is independently in each occurrence halogen, lower haloalkyl, cyano or S(O) 2 -lower alkyl;
R 2 is lower alkyl, lower alkyl substituted by halogen or is (CH 2 ) 0 -cycloalkyl;
R 3 is lower alkyl, NH 2 or amino-substituted by one or two lower alkyl;
X C or N;
n is 1 or 2;
o is 0, 1 or 2; or
an enantiomer thereof, or a pharmaceutically acceptable acid addition salt thereof.

2. The method of claim 1 wherein the disorder is sickle cell disease.

3. The method of claim 1 wherein the disorder is thalassemia.

4. The method of claim 1 wherein the disorder is iron overload syndrome.

5. The method of claim 4 wherein the iron overload syndrome is hereditary hemochromatosis.

6. The method of claim 1 wherein the GlyT1 inhibitor is selected from the group consisting of:
[4-(2-fluoro-4-methanesulfonyl-phenyl)-piperazin-1-yl]-(2-isopropoxy-5-methanesulfonyl-phenyl)-methanone;
[5-methanesulfonyl-2-(2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-[4-(5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl] -methanone;
4-isopropoxy-N-methyl-3-[4-(4-trifluoromethyl-phenyl)-piperazine-1-carbonyl]-benzenesulfonamide; and,
[4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

7. The method of claim 6 wherein the GlyT1 inhibitor is a compound of formula Ia

[4-(3-fluoro-5-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-methanone.

8. A method of treating a hematological disorder characterized by elevated cellular hemoglobulin (Hb) levels comprising administering to a patient in need thereof a therapeutically effective amount of a GlyT1 inhibitor of formula II:

wherein
R 1 is independently in each occurrence halogen, lower alkly, lower haloalkly, alkoxy, cyano or S(O) 2 -lower alkyl;
R 2 is lower alkyl, lower alkyl substituted by halogen or is (CH 2 ) o -cycloalkyl;
R 3 is lower alkyl, NH 2 or amino-substituted by one or two lower alkyl;
X and X 1 are N or C, provided both X and X 1 are not N;
n is 1 or 2;
o is 0, 1 or 2;
or an enantiomer thereof, or a pharmaceutically acceptable acid addition salt thereof.

9. The method of claim 8 wherein the GlyT1 inhibitor is selected from the group consisting of:
[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-(3-trifluoromethyl-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-methanone;
[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-(6-trifluoromethyl-1,3-dihydro-pyrrolo[3,4-c]pyridin-2-yl)-methanone; and,
[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-(5-methoxy-6-trifluoromethyl-1,3-dihydro-isoindol-2-yl)-methanone.

10. The method of claim 9 wherein the GlyT1 inhibitor is a compound of formula IIa

[5-methanesulfonyl-2-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-(3-trifluoromethyl-5,7-dihydro-pyrrolo[3,4-b]pyridin-6-yl)-methanone.

11. The method of claim 8 wherein the disorder is sickle cell disease.

12. The method of claim 8 wherein the disorder is thalassemia.

13. The method of claim 8 wherein the disorder is iron overload syndrome.

14. The method of claim 13 wherein the iron overload syndrome is hereditary hemochromatosis.

Assignees

• Hoffmann La Roche

Inventors

• Alberati Daniela
• Koerner Annette
• Pinard Emmanuel
• Winter Michael

Classifications

• A61P7/06

  Antianaemics · CPC title

• A61P3/12

  for electrolyte homeostasis · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61K31/437 Primary

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title